Unraveling the Mechanisms of Endogenous Tissue Restoration after Bioresorbable Pulmonary Valve Implantation in Sheep

Abstract

Objective: Endogenous Tissue Restoration (ETR) utilizes the regenerative response of the human body to transform an off-the-shelf available, synthetic, absorbable graft into a living functional valve. Recent preclinical studies have shown the principle of ETR for heart valve grafts to be promising1Bennink G Torri S Brugmans M et al.A novel restorative pulmonary valved conduit in a chronic sheep model: Mid-term hemodynamic function and histologic assessment.J Thorac Cardiovasc Surg. 2018; 155 (doi:10.1016/j.jtcvs.2017.12.046.): 2591-2601Google Scholar,2Kluin J Talacua H Smits AIPM et al.In situ heart valve tissue engineering using a bioresorbable elastomeric implant – From material design to 12 months follow-up in sheep.Biomater. 2017; 125 (doi:10.1016/j.biomaterials.2017.02.007.): 101-117Google Scholar. However, further detailed knowledge on the underlying mechanisms of the material-driven regenerative response remains elusive. The goal of the present study was to gain a mechanistic understanding of these processes by histopathological analysis of ETR heart valves. Methods: In this study, Xeltis Pulmonary Valved Conduits (XPV, Xeltis B.V., Eindhoven, The Netherlands) implanted in an ovine model were analyzed. Explanted valves (follow-up time: 2, 6, 12 (N=5 per timepoint) and 24 months (N=2)) were embedded in paraffin and sectioned longitudinally. Spatiotemporal analysis was performed using a comprehensive sheep-specific antibody panel3Dekker S van Geeman D van den Bogaerdt AJ et al.Sheep-specific immunohistochemical panel for the evaluation of regenerative and inflammatory processes in tissue-engineered heart valves.Front. Cardiovasc. Med. 2018; 5 (doi:10.3389/fcvm.2018.00105.): 105Google Scholar. Results: Detailed knowledge on graft absorption as well as neo-tissue formation and a better understanding of cellular influences was obtained. Interestingly, foreign body giant cells were located within the graft material at iNOS-rich degradation and tissue remodeling sites in the hinge region of the leaflet, starting as early as 2 months after implantation. In the conduit material, on the other hand, foreign body giant cells remained on the outer layers with only limited infiltration into the scaffold material. Interestingly, at the same time point vascularization was observed throughout the conduit material. Extracellular matrix components, such as collagens and elastin were formed in a highly heterogeneous fashion, suggesting an important role for hemodynamic loads on the inflammatory and regenerative processes. Conclusions: Our results enhance the mechanistic understanding of material-driven endogenous tissue restoration. These findings also highlight, the importance of the micro-environment imposed by the graft material on the regenerative response towards a biomaterial. KEYWORD: ICTEHV-O-02 The authors do not declare any conflict of interest.